The discovery of new and improved catalysts is a fundamental goal in chemistry, and in particular in the field of combinatorial catalysis. There is also a need to improve chemical reactions generally, including those without catalysts. Chemists in academia and industry have responded to constant pressures to make reactions more efficient and more practical by developing techniques to screen organic reactions to determine the efficacy of various catalysts of interest and optimize various reaction parameters. These screening techniques are designed to identify the effectiveness of a catalyst or other variable in a reaction by monitoring a certain parameter or aspect of a reaction. Of particular convenience are screening systems that allow for the continuous monitoring of a series of reactions, without the need to withdraw aliquots and work these up prior to analysis.
Gas and liquid chromatography have frequently been employed in conjunction with time-point detection systems. Although chromatography-based methods (i.e. GC or HPLC) are among the most common catalyst screening tools used they do not conveniently give kinetic profiles of the reaction being screened. This is because these are time-point assays so each [product] vs. time data point requires taking an aliquot out of the reaction working it up, then quantitating the product. Steven J. Taylor and James P. Morken in Catalytic Diastereoselective Reductive Aldol Reaction: Optimization of Interdependent Reaction. Variables By Arrayed Catalyst Evaluation, J. Am. Chem. Soc. (1999) 121: 12202, investigated the efficacy of transition metal catalysts in catalyzing the stereoselective reductive coupling of α,β-unsaturated esters and aldehydes. The reactions were allowed to proceed for 16 hours and analyzed by GC and compared to an internal standard to determine relative conversion and stereoisomer ratios. Although relative conversion and stereoisomer ratios could be determined and compared for all of the reactions at the completion of the reaction, the relative rates at which the reactions proceeded during the 16 hours were not determined, because to do so would have required physically taking multiple time point quenches of each reaction and analyzing each one by GC or HPLC. In Ti-Catalyzed Region-and Enantioselective Synthesis of Unsaturated a-Amino Nitriles, Amides, and Acids. Catalyst Identification through Screening of Parallel Libraries, J. Am. Chem. Soc. (2000) 122: 2567, Porter, James R. et al. investigated the titanium catalyzed enantioselective addition of cyanide to α,β-unsaturated aryl imines. The enantioselectivity and conversion were determined by chiral HPLC. However, this determination was made only at the completion of the reaction. The procedure as described by the authors does not provide a means for comparison of the kinetics of the reactions. Thus, while the yield and enantioselectivity of reactions can be determined using gas or liquid chromatography with a chiral stationary phase, relative rate kinetic information for the reactions is not readily available.
Another such screening method is IR thermography. In Thermographic Selection of Effective Catalysts from an Encoded Polymer-Bound Library (Science (1998) 280:267-70), Steven J. Taylor and James P. Morken, developed a method for the evaluation of multifunctional catalysts bound to polymers for the catalysis of a simple esterification reaction. Parallel to this work, the group of Manfred Reetz developed a similar technique for examining kinetic resolutions of alcohols by lipase-mediated acylation and resolution of epoxides by ring-opening using Jacobsen-like catalysts (M. T. Reetz, M. H. Becker, K. M. Kühlung, A. Holzwarth Angew. Chem. Int. Ed. 1998, 37, 2647-2650). Utilizing the phenomenon that most chemical reactions have a measurable heat of reaction ΔHro, the effectiveness of catalysts in a library of catalysts was evaluated using a parallel library assay. The most active catalyst was identified by the greatest temperature change, utilizing IR thermography. This method, however, suffers from the limitation that there is no direct evidence of product formation and there is certainly no readily available means of identifying the nature of the product formed. Thus, undesired reactions often are exothermic and would lead to “false positives” in this screen. The Reetz group later showed that endothermic reactions might also lend themselves to IR thermographic screening (M. T. Reetz, M. H. Becker, M. Leibl, A. Fürstner, Angew. Chem. Int. Ed. 2000, 39, 1236-1239). Here the most active catalyst is to produce the greatest heat uptake. In the reaction studied, ring-closing metathesis, evaporation of a volatile byproduct, ethylene, was also endothermic. While this turned out to enhance the signal in this case, it points to another potential source of “false positives” in such a screen.
More elaborate methods of screening have used fluorescence or color changes of substrates to screen for catalysts and optimize variables in chemical reactions. In High-Throughput Screening of Heterogeneous Catalysts by Laser-Induced Fluorescence Imaging, J. Am. Chem. Soc. (2000) 122: 7422, Hui Su and Edward S. Yeung use laser-induced resonance-enhanced fluorescence imaging (LIFI) as a screening method for heterogeneous catalysts for a reaction. This is a high throughput in situ screening method providing micrometer scale spatial resolution and millisecond temporal resolution. LIFI is only applicable to fluorescent species and appears to be most useful for reactions producing volatile products. This method cannot be directly employed for most reactions of interest to the organic chemist, as most reactants do not contain a fluorophore or lead to a fluorescence change.
In A Fluorescence-Based Assay for High-Throughput Screening of Coupling Reactions. Application to Heck Chemistry, J. Am. Chem. Soc.(1999) 121:2123, a screening procedure was followed whereby a substrate possessing an attached fluorophore was reacted with a second molecule that is attached to a solid support. Authors K. H. Shaughnessy et al. employed the fluorescence based screening method to discover new phosphines for Heck chemistry. An acrylate containing an attached coumarin was reacted with an aryl halide supported on a cross-linked polystyrene resin in the presence of a transition metal catalyst. The calorimetric assay was able to be conducted in a high throughput fashion and took significantly less time to conduct than the gas chromatography used by the authors to confirm that their fluorescence based technique was accurate in identifying the most active ligands for the Heck coupling of aryl bromides and chlorides. Thus, in most instances, the substrate for a reaction of interest will have to be modified by the installation of a chromophore in order to employ this method. Screening results obtained for this significantly modified substrate, often containing a highly conjugated appendage, will not necessarily be valid for more typical, non-fluorescent substrates. Of course, additional synthetic chemistry is also often required to synthesize requisite “chromophore-tagged” substrates.
In Reactive Dyes as a Method for Rapid Screening of Homogeneous Catalysts, (1998) J. Am. Chem. Soc. 120: 9971, Alan C. Cooper et al. describe the use of reactive dyes to assess the activity of various catalysts. Potential catalysts for alkene and imine hydrosilation were screened by modifying the substrates of the reactions by incorporation of reactive dyes, which are “bleached” or change color upon undergoing a catalytic reaction. There is, in fact, a significant change or alteration of the dye color due to the saturation of a reactive functionality which disrupts conjugation between an electron donating and an electron accepting functional group. The authors identify an inherent limitation in the procedure described in their article on page 9972 “The bleaching process indicates a change has taken place, such as loss of conjugation between A and D groups, but does not prove that hydrosilation is the cause.” The authors confirmed that the color change was due to the hydrosilation of the dye by analyzing the dye through the use of a conventional reaction in which the hydrosilation of the dye was known to occur and analyzing the dye by NMR spectroscopy. However, in at least one case, a false positive was detected, wherein the presumed hydrosilylation product was, in fact, a hydrogenation product (Pure Applied Chemistry 2001, 73, 119-128). In Discovery of Novel Catalysts for Allylic Alkylation with a Visual Colorimetric Assay, Angew. Chem. Int. Ed., (1999) 38, 3163, Olivier Lavastre and James P. Morken describe a calorimetric technique for parallel analysis of catalysts for allylic alkylation. The technique utilizes the phenomenon that colorless 1-naphthol will undergo electrophilic aromatic substitution with a diazonium salt to give a bright red orange azo dye product. Thus, the release of 1-naphthol as an allylic leaving group can be followed by monitoring azo dye formation. Although active catalysts could be identified by simple visual inspection, parallel UV analysis was employed to assess catalysts possessing similar activity. These methods, too, though of utility, require substantial substrate alteration and assume that the results obtained for “chromophore-tagged” substrates will be valid for more typical substrates. The latter experiment has a further complication in that the diazonium salt itself is quite reactive toward nucleophiles and so, in this case, was actually added only after the allylic substitution reaction had taken place. For this technique to provide for a continuous assay of product formation versus time, reactions will have to be found that are compatible with the presence of diazonium salts.
The move from the more deliberate, traditional approach to catalyst discovery to combinatorial approaches, has spurred great interest in the development of parallel screening methods. As Crabtree recently put it, ideally one seeks “an appropriate chemical sensor in a rapid parallel assay to detect rate and perhaps selectivity.” There is currently great interest in “combinatorial catalysis,” especially that involving transition metal (TM) catalyzed reactions, for which reaction discovery and optimization often involve varying (i) the metal; (ii) the ligand (type, structure and stoichiometry) and (iii) the substrate structure.
The present invention overcomes some of the limitations possessed by the prior art processes. The process of the present invention provides for direct evidence of product or expected stoichiometric byproduct formation that is not available with some prior art techniques such as the IR thermography method. The present invention also provides for relative rate profiles that are not readily provided by time-point detection systems employing gas or liquid chromatography for product separation. Furthermore, the monitoring process of the present invention does not require altering the substrate by installing a chromophore or a fluorophore as fluorescence assays and calorimetric assays involve. Such alterations may be cumbersome and time-consuming and may lead to screening results that are not applicable to the actual (e.g., non-fluorescent) substrate of interest.